1. Field of the Invention
The present invention relates to freeze-dried dosage forms and methods of preparing freeze-dried dosage forms.
2. Description of the Prior Art
Freeze-drying is a well known method of drying heat-sensitive materials in order to protect them from thermal damage. In the past, preparations containing active agents, such as pharmaceuticals, nutrients, diagnostics, fertilizers and insecticides, have been prepared by freeze-drying aqueous solutions or suspensions containing these active ingredients. Various freeze-dried dosage forms and methods for preparing such dosage forms are disclosed in United Kingdom Patent No. 1,548,022 and U.S. Pat. Nos. 4,490,407 and 4,642,903.
The inventors have determined that there are problems associated with the preparation of freeze-dried dosage forms containing water soluble active agents by means of the prior art techniques. Specifically, the inventors have found that the addition of water soluble active agents into a conventional freeze-dried carrier matrix reduces the physical stability of the resulting freeze-dried dosage form. The presence of water soluble active agents caused shrinkage, collapse and softening of the dosage form at increased rates and at lower relative humidities than for conventional freeze-dried dosage forms containing water insoluble active agents or for placebo freeze-dried dosage forms.
It is believed by the inventors that solutions or suspensions containing water soluble active agents may exhibit eutectic freezing characteristics. As the temperature of such a solution or suspension falls below 0.degree. C., water will crystallize as ice, thereby causing an increase in the concentration of the active agent in the solution or suspension. As the temperature is lowered, ice crystallizes out until at a given temperature (the eutectic temperature), the concentration reaches the eutectic concentration and a eutectic solid forms. The eutectic solid is a mixture of ice crystals and the active agent. The eutectic temperature and concentration are independent of the initial concentration of the active agent in the solution or suspension. The volume of the eutectic solid, however, is dependent upon the initial concentration of the active agent. If the initial active agent concentration is high, then the active agent will crystallize out as the temperature of the solution or suspension falls, thereby reducing the active agent concentration of the solution or suspension until the eutectic solid forms at the eutectic temperature and concentration.
It is believed by the inventors that in order to achieve satisfactory freeze-drying of a solution or suspension containing a water soluble active agent, the solution or suspension must be frozen to or below the eutectic temperature and must remain below the eutectic temperature during drying. If the temperature is allowed to rise above the eutectic temperature, the eutectic solid melts. If the eutectic volume is small, this melting causes slow collapse of the resulting freeze-dried dosage form after drying. If the eutectic volume is large, the resulting freeze-dried dosage form exhibits excessive shrinkage and reduced physical stability. Since it is often impractical and expensive to carry out the freeze-drying process below the eutectic temperature, it has been difficult, if not impossible, to prepare satisfactory freeze-dried dosage forms containing water soluble active agents using conventional freeze-drying techniques.
The problems associated with freeze-drying water soluble active agents are not limited to active agents that form true eutectic compositions. Solutions or suspensions containing water soluble active agents may also exhibit the characteristics of glassy compositions. If the temperature of such a composition rises above the glass point, the glass flows or melts, resulting in the collapse or destruction of the freeze-dried dosage form.
The inventors have determined that the physical stability of a conventionally prepared freeze-dried dosage form containing a water soluble active agent may be enhanced by increasing the diameter of the freeze-dried dosage form. This in turn reduces the concentration of the active agent within the dosage form and alleviates the stability problems to some degree. However, this technique is quite limited in that the size of the dosage forms, especially those intended for oral administration, must not exceed a relatively small maximum size range. Furthermore, increasing the dosage size is not economical. The inventors have also determined that the presence of flavoring and sweetening agents renders conventional freeze-dried dosage forms containing water soluble active agents more stable. However, the presence of these additives does not completely alleviate the collapse, shrinkage and physical instability that results from using conventional freeze-drying techniques.
Another problem with trying to produce freeze-dried dosage forms incorporating a water soluble active agent is that the requisite freeze-drying times may be lengthened, thereby increasing the cost of producing the dosage forms. Although reducing the concentration of the active agent in the dosage form may minimize these adverse effects, this causes a corresponding increase in unit size in order to maintain the same effective unit dosage amount. This increase in size also contributes to an increase in processing costs. Thus, the use of conventional freeze-drying to produce dosage forms is practically limited to active agents that are water insoluble and there is a need for an improved freeze-dried dosage form for use with water soluble active agents.
Ion exchange resins are well known. These resins are capable of exchanging a cation or an anion for a variety of ions brought into contact with the resin. In the context of pharmaceutical active agents, it is known that ion exchange resins may be bonded to pharmaceuticals to form pharmaceutical/resin complexes having sustained release characteristics. See U.S. Pat. Nos. 2,990,332; 3,143,465; and 4,221,778; Borodkin et al., "Interaction of Amine Drugs with a Polycarboxylic Acid Ion-Exchange Resin," J. Pharm. Sci. 59(4): 481-486 (1970); Hinsvark et al., "The Oral Bioavailability And Pharmacokinetics Of Soluble And Resin-Bound Forms Of Amphetamine And Phentermine in Man," J. Pharmacokinetics And Biopharmaceutics 1(4): 319-328 (1973); Schlichting, "Ion Exchange Resin Salts For Oral Therapy I, Carbinoxamine," J. Pharm. Sci. 51(2): 134-136 (1962); Smith et al., "The Development Of A Liquid Antihistaminic Preparation With Sustained Release Properties," J. Amer. Pharm. Assoc. 49(2): 94-97 (1960); Hirscher et al., "Drug Release From . . . Cation Exchange Resins," J. Amer. Pharm. Assoc. NS2(2): 105-108 (1962); Amsel et al., "Dissolution And Blood Level Studies With a New Sustained Release System," R & SDC Proceedings 3:93-106 (1980); Amsel et al., "Unique Oral Controlled Release Systems: In Vivo Drug Release Pattern," (unpublished paper). In addition, it is known that ion exchange resins may be bound to pharmaceutical active agents in order to eliminate taste and odor problems in oral pharmaceutical dosage forms. See Borodkin et al., "Polycarboxylic Acid Ion-Exchange Resin Adsorbates for Taste Coverage in Chewable Tablets," J. Pharm. Sci. 60(10): 1523-1527 (1971); Specification Sheets for Amberlite IRP-64, Amberlite IRP-69 and Amberlite IRP-276, published by Rohm and Haas Company (1983).